Globally, approximately 70% of new HIV infections and 75% of AIDS deaths occur in sub-Saharan Africa, and at least 90% of infections in Africa occur through heterosexual transmission. Three randomized controlled trials (RCTs) have shown that medical male circumcision (MMC) reduces the risk of HIV acquisition in African men by ~60% over 18-24 months, and the WHO has endorsed MMC as an effective HIV prevention strategy. Despite this, important questions concerning the efficacy of MMC for HIV prevention remain. It is not known whether the protective effect of MMC will be sustained longer than the brief duration of the trials or than the 42 months of follow-up of Kenyan men reported recently by ourselves. There was little evidence that circumcised men in the trials increased their HIV risk behaviors after circumcision. However, risk compensation by circumcised men or their female sex partners as MMC becomes more widely promoted, could erode the protective effect of MMC. In our RCT, MMC more than halved the risk of HIV seroconversion [RR = 0.41] among men aged 18-24 years in Kisumu, Kenya. Despite this, the 2-year HIV seroconversion rate was 2.1% for circumcised men. The combined incidence of gonorrhea, chlamydia, and trichomonas was high (8.34 per 100 person-years), and did not differ by circumcision status. The incidence of genital ulcer disease was halved for circumcised men [RR=0.46], but the 2-year incidence of HSV-2 in the cohort was 10.5% and did not differ by circumcision status. The objectives of this study are to estimate up to 96 months post-enrollment, the long term effect of MMC on men's risk of HIV and STI acquisition, to measure female partners'genital tract infections and symptoms by partner's circumcision status, and to assess secular and individual changes in sexual behaviors and risk perceptions in men and women. To achieve these objectives, we will continue to observe the 1483 men remaining in the cohort, recruit 804 additional men, and recruit 650 female sex partners. We will assess the incidence of HIV, multiple STIs, genital morbidity, and behavioral practices every 6 months over a 3.5-year period. We will address 3 specific aims: (1) to determine the effects of MMC on HIV and sexual behavior up to 96 months post-circumcision;(2) to determine the effects of MMC on STI incidence and genital tract morbidity in female sex partners;(3) to determine secular changes in sexual behaviors and endorsement of circumcision. The proposed expansion of the cohort capitalizes on existing infrastructure and expertise, ensuring efficiency. Furthered collaboration with Kenyan investigators advances the national and community ownership. This study will add to our understanding of the interactions between biological mechanisms and behaviors, so that new solutions that effectively and sustainably prevent sexual transmission of HIV and STIs may be implemented. To understand whether MMC can achieve further gains in population-level reduction of HIV and STIs, assessment of its long term effects on men's risk of HIV seroconversion, on female partners'genital tract infections and symptoms, and on secular and individual changes in sexual behaviors is crucial. PUBLIC HEALTH RELEVANCE: Despite the protective effect of circumcision against HIV acquisition in heterosexual men, risk of HIV and STIs remain high. To understand whether circumcision can achieve further gains in population-level reduction of HIV and STIs, assessment of its long term effects on men's risk of HIV seroconversion, on female partners'genital tract infections and symptoms, and on secular and individual changes in sexual behaviors is crucial. The knowledge gained will assist Kenyan and international policymakers to design and implement bio-behavioral interventions that effectively and sustainably reduce sexual transmission of HIV and STIs.